16-year study is further evidence that estrogen replacement may be protective against Alzheimer's disease

Scientists at the National Institute on Aging (NIA) and Johns Hopkins Bayview Medical Center have shown that a history of estrogen replacement therapy (ERT) in women after menopause was associated with a reduction, by over 50 percent, in the risk of developing Alzheimer's disease. The study is important because it is one of the first long-term analyses of estrogen's effect on Alzheimer's disease. Although these results suggest that estrogen use may reduce the risk of Alzheimer's disease, NIA scientists emphasize that controlled clinical trials will be required to directly test this possibility.

Recent studies from the NIA have pointed to a variety of safe and commonly available substances that may be protective against Alzheimer's disease. Two of these are Vitamin E and non-steroidal anti-inflammatory drugs such as ibuprofen. Further evidence of estrogen's protective effect adds another element to what scientists hope will be an arsenal of substances that could delay or prevent the onset of Alzheimer's disease.

The NIA's Baltimore Longitudinal Study on Aging (BLSA), now entering its 40th year of observing many aspects of aging in over 2,000 people, gives this study of estrogen replacement (472 women observed over 16 years) its particular power. This study, reported in the June, 1997 issue of Neurology (Vol. 48, No. 6) was conducted by Claudia Kawas, MD, of Johns Hopkins Bayview Medical Center, and by E. Jeffrey Metter, MD, Susan Resnick, PhD, and Alan Zonderman, PhD, of the NIA, and several other NIA and Johns Hopkins investigators.

According to Dr. Metter, "a long-term study such as the BLSA significantly minimizes many of the problems found in short-term case-control studies previously done on ERT effects on Alzheimer's disease. The many and varied resources of the BLSA are put to excellent use in a study such as this that examines the powerful effects of a substance such as estrogen on the aging brain." By examining the women in this study during a two-and-a-half day intensive visit to the NIA every two years, the investigators were able to assess ERT use and any onset of dementia through a battery of physical and cognitive tests. Only oral or transdermal ERT were assessed since estrogen creams do not significantly increase circulating levels of estrogen.

According to Dr. Kawas "this finding gives us additional evidence that estrogen may play a role in warding off the onset of this devastating disease." Only a few months ago, a study by Dr. Walter Stewart, Kawas, Metter and others found a 55 percent reduction in risk against Alzheimer's disease in BLSA participants who took non-steroidal anti-inflammatory (NSAIDs) drugs such as ibuprofen and naprosyn. When comparing NSAIDs and ERT, each reduced the risk for Alzheimer's by 50 to 55 percent. A larger study needs to be conducted to see if there might be added benefit from taking both substances and to assess the benefits of prolonged ERT use.

According to Dr. Metter, "estrogen is a substance that is worthy of further study as a protective drug against Alzheimer's disease because it has been shown to exhibit both antioxidant and anti-inflammatory activity, lower ApoE levels in plasma (certain forms of the ApoE gene have been linked to an increased risk of Alzheimer's in some people), as well as to enhance the growth of certain neurons that release a crucial brain transmitter known as acetylcholine."

As Dr. Kawas confirms, "estrogen has been shown to have a direct effect on brain structure and function, particularly for women. 'Designer' estrogen, drugs that are currently being developed by a number of pharmaceutical companies, could minimize estrogen's feminizing and other unwanted side effects and provide a potent strategy for both men and women in delaying or reducing death due to Alzheimer's disease in a large segment of the aging population. If these drugs can be synthesized, only with double-blinded clinical trials will we really know if these substances will be effective in the fight against Alzheimer's disease."

Also contributing to this study were Susan Resnick, PhD, Alan Zonderman, Ph.D., C. Bacal, MPH, PA-C, and D. Donnell Lingle, MSN, CRNP, (NIA), A. Morrison, MS, RN, and M. Corrada, ScM (Johns Hopkins University School of Medicine) and R. Brookmeyer, Ph.D. (Johns Hopkins University School of Hygiene and Public Health).

The National Institute on Aging, one of the 18 Institutes which make up the National Institutes of Health, leads the Federal effort supporting basic, clinical, epidemiological and social research on Alzheimer's disease and the special needs of older people.

For more information on the NIA and aging in general, please visit our web site at www.nia.nih.gov[1] . General information is also available from our resource center by calling, toll-free, 1-800-222-2225. Information and brochures on Alzheimer's disease is available from the Alzheimer's Disease Education And Referral (ADEAR) Center at 1-800-438-4380.